This invention relates to novel substituted tricyclic organic compounds useful for inhibiting sPLA2 mediated release of fatty acids for conditions such as septic shock.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been thoroughly described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, pp. 5335-5338, 1989; and xe2x80x9cStructure and Properties of a Human Non-pancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2 such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc.
It is desirable to develop new compounds and treatments for sPLA2 induced diseases.
This invention provides tricyclic compounds as depicted in the general formula (I) below: 
wherein;
Z is xe2x80x94Cxe2x95x90O, xe2x80x94CH2,
A is xe2x80x94O(CH2)fxe2x80x94; xe2x80x94NH(CH2)fxe2x80x94; xe2x80x94S(CH2) fxe2x80x94; xe2x80x94(CH2)f, where f is 1 to 3; xe2x80x94CHxe2x95x90CHxe2x80x94; 
xe2x80x83or xe2x80x94(La)xe2x80x94, where xe2x80x94(La)xe2x80x94is an acid linker having an acid linker length of 1 to 7;
R1xe2x80x2 is xe2x80x94NHNH2 or xe2x80x94NH2;
R2xe2x80x2 is xe2x80x94CO2H; xe2x80x94CO2(C1-C4)alkyl; 
xe2x80x83where R6 and R7 are each independently xe2x80x94OH or xe2x80x94O(C1-C4)alkyl; tetrazolyl; xe2x80x94CONR9R10, where R9 and R10 are independently hydrogen, xe2x80x94CF3, xe2x80x94(C1-C4)alkyl, phenyl or xe2x80x94(C1-C4)alkylphenyl; xe2x80x94SO2R15; xe2x80x94CONHSO2R15, where R15 is hydrogen, aryl, xe2x80x94(C1-C6)alkyl or xe2x80x94CF3; or phenyl substituted with xe2x80x94CO2H or xe2x80x94CO2(C1-C4)alkyl;
R3xe2x80x2 is selected from non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents;
R4xe2x80x2 is selected from groups (a) and (b) where;
(a) is xe2x80x94(C5-C20)alkyl, xe2x80x94(C5-C20)alkenyl, xe2x80x94C5-C20)alkynyl, carbocyclic radicals, or heterocyclic radicals, or
(b) is a member of (a, substituted with one or more independently selected non-interfering substituents;
or a pharmaceutically acceptable racemate, solvate, optical isomer, prodrug derivative or salt thereof.
These substituted tricyclics are effective in inhibiting human sPLA2 mediated release of fatty acids.
This invention is also a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluteness, carriers and excipients.
This invention is also a method of inhibiting sPLA2 comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.
According to a further aspect of the present invention, there is provided a method of selectively inhibiting sPLA2 in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of formula I.
This invention, further provides a compound of Formula I for use as a medicament in the treatment of inflammatory diseases such as sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, asthma, rheumatoid arthritis, osteoarthritis, acute bronchitis, chronic bronchitis, Inflammatory Bowel Disease, apoptosis, stroke, cystic fibrosis, allergic rhinitis, acute bronchiolitis, chronic bronchiolitis, gout, spondylarthropathris, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with xe2x80x9cvasculitic syndromesxe2x80x9d, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec""s granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing) miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat""s Disease, systemic lupus eryzhrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
As used herein, the term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like. The term xe2x80x9calkylxe2x80x9d includes xe2x80x94(C1-C2)alkyl, xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C6)alkyl, xe2x80x94(C5-C14)alkyl, and xe2x80x94(C1-C10)alkyl.
The term xe2x80x9calkenylxe2x80x9d as used herein represents an olefinically unsaturated branched or linear group having at least one double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl as well as dienes and trienes of straight and branched chains.
The term xe2x80x9calkynylxe2x80x9d denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as well as di- and tri-ynes.
The term xe2x80x9chaloxe2x80x9d means chloro, fluoro, bromo or iodo.
The term xe2x80x9cxe2x80x94(C1-C4)alkoxyxe2x80x9d, as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups, attached to the remainder of the molecule by the oxygen atom.
The term xe2x80x9cphenyl(C1-C4)alkylxe2x80x9d refers to a straight or branched chain alkyl group having from one to four carbon atoms attached to a phenyl ring which chain is attached to the remainder of the molecule. Typical phenylalkyl groups include benzyl, phenylethyl, phenylpropyl, phenylisopropyl, and phenylbutyl.
The term xe2x80x9carylxe2x80x9d means an aromatic carbocyclic structure having six to ten carbon atoms. Examples of such ring structures are phenyl, naphthyl and the like.
The term, xe2x80x9cheterocyclic radicalxe2x80x9d, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyridyl, thienyl, fluorenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pryidinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.
The term xe2x80x9ccarbocyclic radicalxe2x80x9d refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexeyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), 
where n is an integer from 1 to 8.
The term, xe2x80x9cnon-interfering substituentxe2x80x9d, refers to radicals suitable for substitution at positions 5 or 6 on the tricyclic nucleus (as depicted in Formula I) and radical(s) suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are hydrogen, xe2x80x94(C1-C14)alkyl, xe2x80x94(C2-C6)alkenyl, xe2x80x94(C2-C6)alkynyl, xe2x80x94(C7-C12)aralkyl, xe2x80x94(C7-C12)alkaryl, xe2x80x94(C3-C8)cycloalkyl, xe2x80x94(C3-C8)cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C2-C6)alkenyloxy, xe2x80x94(C2-C6)alkynyloxy, xe2x80x94(C1-C12)alkoxyalkyl, xe2x80x94(C1-C12)alkoxyalkyloxy, xe2x80x94(C1-C12)alkylcarbonyl, xe2x80x94(C1-C12)alkylcarbonylamino, xe2x80x94(C1-C12)alkoxyamino, xe2x80x94(C1-C12)alkoxyaminocarbonyl, xe2x80x94(C1-C12)alkylamino, xe2x80x94(C1-C6)alkylthio, xe2x80x94(C1-C12)alkylthiocarbonyl, xe2x80x94(C1-C6)alkysulfinyl, xe2x80x94(C1-C6)alkylsulfonyl, xe2x80x94(C1-C6)haloalkoxy, xe2x80x94(C1-C6)haloalkylsulfonyl, xe2x80x94(C1-C6)haloalkyl, xe2x80x94(C1-C6)hydroxyalkyl, xe2x80x94(CH2)nCN, xe2x80x94(CH2)nNR9R10, xe2x80x94C(O)O(C1-C6alkyl), xe2x80x94(CH2)nO(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2)R16, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, pyridyl, amino, amidino, halo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nCO2H, cyano, cyanoguanidinyl, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, furyl, thiophenyl xe2x80x94COR9, xe2x80x94CONR9R16, xe2x80x94NR9R10, xe2x80x94NCHCOR9, xe2x80x94SO2R9, xe2x80x94OR9, xe2x80x94SR9, CH2SO2R9, tetrazolyl; tetrazolyl substituted with xe2x80x94(C1-C6)alkyl, phenyl or xe2x80x94(C1-C4)alkylphenyl; xe2x80x94(CH2)nOSi(C1-C6)3alkyl and (C1-C6)alkylcarbonyl; where R9 and R10 are independently hydrogen, xe2x80x94CF3, phenyl, xe2x80x94(C1-C4)alkyl, or xe2x80x94(C1-C4)alkylphenyl, where n is from 1 to 8, where R15 is xe2x80x94(C1-C6)alkyl, xe2x80x94CF3, naphthyl or xe2x80x94(CH2)sphenyl, and where s is from 0 to 5.
A preferred group of non-interfering substituents include hydrogen, xe2x80x94(C1-C6)alkyl, xe2x80x94(C2-C6)alkenyl, xe2x80x94(C2-C6)alkynyl, xe2x80x94(C3-C8)cycloalkyl, xe2x80x94(C1-C6)alkoxy, halo or xe2x80x94(C1-C4)alkyl phenyl.
Another preferred group of non-interfering substituents include hydrogen, halo, xe2x80x94(C1-C3)alkyl, xe2x80x94(C3-C4)cycloalkyl, xe2x80x94(C3-C4)cycloalkenyl, xe2x80x94O(C1-C2)alkyl and xe2x80x94S(C1-C2)alkyl.
The words, xe2x80x9cacid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(La)xe2x80x94.
The words, xe2x80x9cacid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(La)xe2x80x94 that connects the 7 or 8 position of the tricyclic nucleus with the remainder of the chain. The presence of a carbocyclic ring in xe2x80x94(La)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(La)xe2x80x94. Illustrative acid linker groups are; 
where t is 1 to 5, Q is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94Sxe2x80x94, and R84 and R85 are each independently selected from hydrogen, xe2x80x94(C1-C10)alkyl, aryl, xe2x80x94(C1-C10)alkaryl, xe2x80x94(C1-C10)aralkyl, carboxy, carbalkoxy, and halo. When t is one (1), groups (a), (b), and (d) have acid linker lengths of 3, 3, and 2, respectively.
The salts of the above tricyclics are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic functional groups, various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include but are not limited to the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Sodium salts are preferred. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66:1-19 (1977)).
Compounds of the invention may have chiral centers and exist in optically active forms. R- and S-isomers and racemic mixtures are contemplated by this invention. A particular stereoisomer may be prepared by known methods using stereospecific reactions with starting materials containing asymmetric centers already resolved or, alternatively, by subsequent resolution of mixtures of stereoisomers using known methods.
Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, such as, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic esters (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. Other preferred esters include morpholinoethyloxy, diethylglycolamide and diethylaminocarbonylmethoxy. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
The term xe2x80x9cacid protecting groupxe2x80x9d is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an acid group from participating in a reaction carried out on some other functional group in the molecule, but which can be removed when it is desired to do so. Such groups are discussed by T. W. Greene in chapter 5 of Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981, incorporated herein by reference in its entirety.
Examples of acid protecting groups include ester or amide derivatives of the acid group, such as, methyl, methoxymethyl, methyl-thiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenyl, aryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, t-butyl, cyclopentyl, triphenylmethyl, diphenylmethyl, benzyl, trimethylsilyl, N,N-dimethyl, pyrrolidinyl, piperidinyl, or o-nitroanilide. A preferred acid-protecting group is methyl.
A preferred subclass of compounds of formula (I) are those wherein R4xe2x80x2, is selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), 
where n is a number from 1 to 8.
Particularly preferred are compounds wherein R4xe2x80x2 is selected from the group consisting of 
where R17 is a radical independently selected from halo, xe2x80x94(C1-C10)alkyl, xe2x80x94(C1-C10)alkoxy, xe2x80x94Sxe2x80x94(C1-C10 alkyl), and xe2x80x94(C1-C10)haloalkyl, and w is a number from 0 to 5.
Another preferred subclass of compounds of Formula (I) are those wherein A is a substituent having an acid linker with an acid linker length of 2 or 3 and the acid linker group, xe2x80x94(La)xe2x80x94, for A is selected from a group represented by the formula; 
where Q is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94Sxe2x80x94, and R84 and R85 are each independently selected from hydrogen, xe2x80x94(C1-C10)alkyl, aryl, xe2x80x94(C1-C10)alkylaryl, xe2x80x94aryl(C1-C10)alkyl, carboxy, carbalkoxy, and halo.
Most preferred are compounds where the acid linker, xe2x80x94(La)xe2x80x94, for A is selected from the specific groups; 
Another preferred subclass of compounds of formula (I) are those wherein A is a substituent having an acid linker with an acid linker length of 3 to 8 atoms and the acid linker group, xe2x80x94(La)xe2x80x94, for A is selected from; 
where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94Sxe2x80x94, and R84 and R85 are each independently selected from hydrogen, xe2x80x94(C1-C10)alkyl, aryl, xe2x80x94(C1-C10)alkylaryl, -aryl(C1-C10)alkyl, carboxy, carbalkoxy, and halo.
Another preferred subclass are compounds where the acid linker, xe2x80x94(La)xe2x80x94, for A is selected from the specific groups; 
wherein R84 and R85 are each independently selected from hydrogen, xe2x80x94(C1-C10)alkyl, aryl, xe2x80x94(C1-C10)alkaryl, xe2x80x94(C1-C10)aralkyl, carboxy, carbalkoxy, and halo.
Another preferred group of non-interfering substituents include hydrogen, xe2x80x94O(C1-C4)alkyl, halo, xe2x80x94(C1-C6)alkyl, phenyl, xe2x80x94(C1-C4)alkylphenyl; phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, or xe2x80x94CF3; xe2x80x94CH2OSi(C1-C6)3alkyl, furyl, thiophenyl, xe2x80x94(C1-C6)hydroxyalkyl; or xe2x80x94(CH2)nR8 where R8 is hydrogen, xe2x80x94CONH2, xe2x80x94NR9R10, xe2x80x94CN or phenyl; where R9 and R10 are independently xe2x80x94(C1-C4)calkyl or -phenyl(C1-C4)alkyl and where n is 1 to 8.
Preferred compounds of the invention are those having the general formula (II) 
wherein;
R2 is xe2x80x94CO2H, xe2x80x94CO2(C1-C4 alkyl); 
xe2x80x83tetrazolyl, xe2x80x94CONR9R10; xe2x80x94SO2R15, xe2x80x94CONHSO2R15 or phenyl substituted with xe2x80x94CO2H or xe2x80x94CO2(C1-C4)alkyl, where R6 and R7 are each independently xe2x80x94OH or xe2x80x94O(C1-C4)alkyl, R9 and R10 are each independently hydrogen, xe2x80x94CF3, xe2x80x94(C1-C4)alkyl, phenyl or xe2x80x94(C1-C4)alkylphenyl and R15 is hydrogen, aryl, xe2x80x94(C1-C6)alkyl or xe2x80x94CF3;
R3 is hydrogen, xe2x80x94O(C1-C4)alkyl, halo, xe2x80x94(C1-C6)alkyl, phenyl, xe2x80x94(C1-C4)alkylphenyl; phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, or xe2x80x94CF3; xe2x80x94CH2OSi(C1-C6)3alkyl, furyl, thiophenyl, xe2x80x94(C1-C6)hydroxyalkyl, xe2x80x94(C1-C6)alkoxy(C1-C6)alkyl, xe2x80x94(C1-C6)alkoxy(CC1-C6)alkenyl, xe2x80x94(C1-C6)alkoxy(C1-C6)alkyl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)alkenyl, or xe2x80x94(CH2)nR6, where R8 is hydrogen, xe2x80x94CONH2, xe2x80x94NR9R10, xe2x80x94CN or phenyl, where R9 and R10 are independently hydrogen, xe2x80x94CF3, phenyl, xe2x80x94(C1-C4)alkyl or xe2x80x94(C1-C4)alkylphenyl and n is 1 to 8; and
R4 is xe2x80x94(C5-C14)alkyl, xe2x80x94(C3-C14)cycloalkyl, pyridyl, phenyl or phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94(C1-C4)alkoxy, xe2x80x94CN, xe2x80x94(C1-C4)alkylthio, phenyl(C1-C4)alkyl, xe2x80x94(C1-C4)alkylphenyl, phenyl, phenoxy or naphthyl;
or a pharmaceutically acceptable racemate, solvate, optical isomer, prodrug derivative or salt, thereof.
Preferred Substituents of Compounds of Formula I and II Include the Following:
(a) R1 is xe2x80x94NH2;
(b) R2 is xe2x80x94CO2H or xe2x80x94CO2(C1-C4)alkyl;
(c) R2 is xe2x80x94NH2 or NR9R10 where R9 and R10 are hydrogen, xe2x80x94(C1-C4)alkyl or phenyl (C1-C4)alkyl;
(d) R2 is phenyl substituted with xe2x80x94CO2H or xe2x80x94CO2(C1-C4 alkyl);
(e) R2 is 
xe2x80x83where R6 and R7 are xe2x80x94O(C1-C4 alkyl), or when one of R6 and R7 is xe2x80x94O(C1-C4 alkyl), the other is xe2x80x94OH;
(f) R3 is hydrogen, xe2x80x94O(C1-C4 alkyl) or xe2x80x94(CH2)nR8 where n=2 and R8 is hydrogen or phenyl;
(g) R3 is hydrogen or xe2x80x94O(C1-C4 alkyl);
(h) R3 is xe2x80x94(CH2)nR8 where R8 is xe2x80x94NR9R10, 
xe2x80x83or xe2x80x94CN, where R9 and R10 are xe2x80x94(C1-C4)alkyl;
(i) R3 is hydrogen, xe2x80x94O(C1-C4)alkyl, halo, xe2x80x94(C1-C6)alkyl, phenyl, xe2x80x94(C1-C4)alkylphenyl; phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, or xe2x80x94CF3; xe2x80x94CH2OSi(C1-C6):3alkyl, furyl, thiophenyl, xe2x80x94(C1-C6)hydroxyalkyl; or xe2x80x94(CH2)nR8 where, where R8 is hydrogen, xe2x80x94CONH2, xe2x80x94NR9R10, xe2x80x94CN or phenyl where R9 and R10 are independently hydrogen, xe2x80x94CF3, xe2x80x94(C1-C4)alkyl or xe2x80x94(C1-C4)alkylphenyl and n is 1 to 8;
(j) R4 is phenyl;
(k) R4 is phenyl substituted at the 2- and 6-position of the phenyl ring with xe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy, halo or phenyl;
(l) R4 is phenyl substituted at the 2- or 6-position of the phenyl ring with xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C4)alkoxy, halo or phenyl;
(m) R4 is phenyl substituted at the 3- or 5-position of the phenyl ring with xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C4)alkoxy, halo or phenyl;
(n) R4 is xe2x80x94(C6-C14)alkyl);
(o) A is xe2x80x94OCH2xe2x80x94;
(p) Z is xe2x80x94Cxe2x95x90O;
(q) when A is attached to the remainder of the ring at the 8-position, f is 1; and
(r) when A is attached to the remainder of the ring at the 7-position, f is 3.
Some typical compounds of this invention are provided in Table 1 below, however, such named compounds are not intended to limit the scope of this invention in any way.
For A and R3 the numerical prefix corresponds to the position the substituent is attached to the tricyclic ring
Compounds of the invention can be prepared, generally, as described in Scheme I. Unless otherwise specified, all reactions are preferably run under an inert atmosphere such as nitrogen. The reactions may be monitored for completion by ordinary methods such as by thin layer chromatography. Unless otherwise specified, the reactions may be conducted using any solvent which is inert to the reactants and has adequate solvency for them. 
In a Lewis acid mediated acylation, starting material (1) is treated with a slight molar excess of a weak acid, preferably magnesium perchlorate, then reacted with an appropriately substituted glycidic where R4 is preferably phenyl. The reaction is preferably conducted in an aprotic solvent, preferably acetonitrile, at temperatures of from about 0xc2x0 C. to 50xc2x0 C. The arylglycidic alcohols used in this step are readily available as optically pure compounds [Katsuki, T; Sharpless, K. B. J. Am. Chem. Soc., 1980, 102, 5974] and this reaction is highly stereopspecific. For example, using the 1S, 2S glycidic alcohol will give a final product having the R configuration at position 3, and using the 1R, 2R, glycidic alcohol will provide the final product having the S configuration at position 3 since this position is inverted by the epoxide opening reaction and unaffected during the course of all subsequent reactions.
Conversion of dialcohol (2) to a suitable leaving group is achieved by refluxing with thiolcarbonyl diimidazole in a suitable aprotic solvent such as tetrahydrofuran(THF).
Reductive elimination of the leaving group of (3) to form olefin (4) is accomplished by heating with a suitable reducing agent such as trimethyl, triethyl or triphenyl phosphite. The reaction is preferably conducted at temperatures of from about 50xc2x0 to 120xc2x0 C. for extended periods of time, from about 20 to 24 hours, preferably about 22 hours.
In a two step, one pot reaction, oxidation of (4) is accomplished by treating first with a borane reagent, preferably 9-borobicylo[3.3.1]nonane followed by treatment with hydrogen peroxide in the presence of an excess of a hydroxide base, preferably sodium hydroxide. Lithium hydroxide may also be employed. Reactions maybe run at temperatures of from about xe2x88x9210xc2x0 C. to 250xc2x0 C., preferably at about 0xc2x0 C. Preferably, the reactions are conducted in an aprotic solvent such as THF.
Aromatization of the indole ring may be accomplished by oxidation of (5) with a slight excess, preferably 1.1 equivalents, of 2,3-dichloro-5,6-dicyano-1,4-benzo quinone(DDQ), at temperatures from about 50xc2x0 to 110xc2x0 C., preferably at about 70xc2x0 C. The reaction is substantially complete in about 5 hours.
Conversion of intermediate (6) to the alkylhalide (7) may be achieved by treatment with a reagent of the formula CX4, where X is halo, preferably chlorine, in the presence of an activating agent, preferably triphenylphosphine. The reaction may be conducted at room temperature and requires extended periods of time, up to about 16 hours, for completion.
Free radical cyclization of (7) is generally accomplished by treatment first with a tin hydride reagent such as tributyl tinhydride, in the presence of a free radical initiatior such as 1,1xe2x80x2 azobis(cyclohexanecarbonitrile) (ACN) or 2,2xe2x80x2-azobisisobutyronitrile (AIBN) then with additional aliquots of ACN or AIBN added slowly over a period of about five hours. The reaction is substantially complete about one hour after the last addition of ACN or AIBN. The reaction is preferably conducted in an aprotic, high boiling organic solvent such as degassed toluene, at temperatures of about 110xc2x0 C.
Oxidation of indoline (8) to indole (9) is accomplished as described above, by oxidation with an oxidizing reagent such as DDQ. Other oxidizing agents are also suitable, however if DDQ is utilized, it is critical that a slight excess (about 1:1 equivalents) is employed. The reaction is preferably conducted in an organic solvent such as dioxane, usually under moderate reaction conditions.
Deprotection of the oxy group of (9) is readily accomplished by treatment with an excess of from about 2 to 10 equivalents of boron tribromide. Other suitable deprotecting reagents include, but are not limited to, pyridine hydrochloride, aluminum chloride, ethane thiol and sodium ethane thiolate. Generally, the reaction is run at low temperatures, preferably in the range of from about xe2x88x9210xc2x0 C. to ambient temperature in an inert solvent such as methylene chloride.
Alkylation of the hydroxy group is accomplished by treatment with an alkylating agent of the formula XCH2R2xe2x80x2 (where X is halo and R2xe2x80x2 is preferably xe2x80x94CO2R5, xe2x80x94SO2R5, xe2x80x94P(O)(OR5)2, or xe2x80x94P (O)(OR5)H, where R5 is an acid protecting group or a prodrug function) in the presence of a base. Preferable, an excess of from about 1.1 to 3 equivalents of alkylating agent is employed and from 1 to 4 equivalents of base. Suitable bases include, but are not limited to, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride and lithium hydride.
The reaction is preferably carried out in an organic solvent such is dimethyl formamide or acetone, however other suitable non reactive solvents may be employed. Generally the reaction is run at ambient temperatures.
Acylation and animation of (11) is accomplished by treatment first with oxaly chloride in an alkyl halide solvent, such as chloroform, followed by treatment with ammonia in the form of a gas or an ammonium salt such as ammonium hydroxide. Suitable solvents include protic polar solvents such as ethanol, methanol, dioxane and water. The reaction is preferably conducted at temperatures of from about 20 to 100xc2x0 C. Reduction of the carbonyl can be accomplished catalytically or with hydrides.
The acid may be optionally salified, if desired When A is other than oxygen, compounds of the invention can be prepared as described above, using an appropriately substituted indole as the starting material. See also Dillard, et. al., xe2x80x9cIndole Inhibitors of Human Non-Pancreatic Secretory Phosphilapase A22-Indole-3-Acetamides with Additional Functionalityxe2x80x9d, Journal of Medicinal Chemistry, Vol. 39, No. 26, pp5137-5158, for preparation of compounds where A is other than oxygen and Z is other than carbonyl.